The healthy cartilage of joints (articular cartilage) in humans and other vertebrates is characterized by a columnar growth pattern of chondrocytes, which produce a hyaline cartilage containing predominantly proteoglycans, type II collagen, and water. Articular cartilage provides an effective weight-bearing cushion to prevent bone-to-bone contact of opposing bones in a joint and, thus, is critical to the normal function of the joint. The regeneration of authentic articular cartilage remains a major challenge in modern medicine because the factors initiating cartilage formation, maturation, and healing are poorly understood. Approximately one-half of the knee joints of patients that are examined arthroscopically contain asymptomatic cartilage defects, i.e., most defects in the cartilage do not penetrate completely to the subchondral bone. These “partial thickness defects” in articular cartilage usually are not painful. However, the remaining cartilage at the base of a partial thickness defect may continue to erode and the diameter of the defect may also increase such that the defect eventually progresses to a “full thickness defect” that penetrates to the underlying bone. Such full thickness defects may become large enough that the opposing bones of the joint eventually contact and begin eroding one another leading to inflammation, pain, and degenerative changes, i.e., the classic symptoms of osteoarthritis. Osteoarthritis is a crippling disease that results in joint deformity and that typically affects a patient's quality of life as the patient avoids the pain and instability of using the deformed joint in work and daily living.
Studies of the restoration and healing of joint defects have employed drilling holes in the articular cartilage of animal knee joints. Such defects undergo a form of repair with the formation of a new layer of bone and repair tissue, but the macromolecular organization and the biochemical characteristics of the repair tissue are clearly imperfect as evidenced by the persistence of high levels of type I collagen and the substitution of the cartilage specific proteoglycans with other types, such as dermatan sulfate-containing proteoglycans. The resulting repair tissue is an inferior fibrocartilaginous tissue that exhibits fibrillations and extensive degenerative changes after about three months and that eventually degenerates into a complete loss of tissue integrity and more damage to the joint. Such fibrous repair tissue typically forms at defect sites in all forms of current treatments (see, below). Accordingly, true regeneration of articular cartilage at a defect site in humans and other vertebrates would restore a columnar organization of metabolically active chondrocytes, which produce type II collagen that in combination with certain proteoglycans becomes fully integrated with the cartilage surrounding the defect and thereby restores the full weight bearing capacity of the joint cartilage.
Several procedures are currently in use to treat defects of articular cartilage. A widely used method that seeks to provide repair of a defect site involves debridement of cartilage at the defect site to expose subchondral bone followed by drilling and microfracture (using specialized instruments) to produce tunnels through the subchondral bone to connect the defect site with the bone marrow. Bone marrow cells, which have an aggressive proliferation capacity, then migrate through the tunnels and form fibrocartilage in the defect area. This type of procedure may be performed arthroscopically, which reduces injury to the joint and does not leave a skin scar, may be performed as a one-stage procedure, and is relatively inexpensive. However, the newly formed tissue formed by this procedure has no cartilage architecture, but is entirely made of a fibrocartilage that has a short surviving and low weight bearing capacity. Maximum improvement of symptoms following this procedure may last for two to five years followed by an unsatisfactory longer-term outcome.
Regenerative approaches to restore articular cartilage at a defect site include autologous chondrocyte transplantation (ACT), which implants chondrocytes (alone or in combination with a cartilage matrix) at a defect site, and mosaicplasty, which implants autografts or allografts at a defect site. In ACT, chondrocytes are harvested from a non-weight bearing portion of the joint and expanded in vitro prior to implanting into the defect. In mosaicplasty, osteochondral plugs are harvested from non-weight bearing portions of a joint and inserted into the defect site. Depending on the defect and other considerations, either procedure may be carried out by open surgery or arthroscopically. Although some weight-bearing relief may be achieved for some patients by these procedures, the sites of implantation generally progress to a less organized architecture than healthy hyaline cartilage in combination with a fibrocartilage tissue. Accordingly, such replacement tissue lacks the characteristics and integrity of authentic articular cartilage.
The generally poor results for treating full thickness defects by the procedures described above continue to reinforce the general belief in orthopedic surgery that it is best to not disturb asymptomatic partial thickness defects as current procedures would only remove the remnant of healthy cartilage at a defect site prematurely to introduce an inferior fibrocartilage tissue.
The use of biochemical signaling molecules, such as bone morphogenetic proteins (BMPs), to regenerate cartilage at a defect site has also been studied. For example, cells migrating into a cartilage defect were transformed into chondrocyte-like cells and even produced type II collagen fibers in the presence of a BMP that was exogenously applied to the defect area (Jelic et al., Growth Factors, 19(2): 101-113 (2001)). However, such tissue did not display the characteristic columnar microarchitecture of authentic articular cartilage and thus lacked the biomechanical and structural properties that enable authentic articular cartilage to function and persist in the joint.
Clearly, needs remain for joint preserving procedures to treat partial thickness defects in a manner that restores the characteristic structural and biochemical properties of healthy articular cartilage and thereby inhibit or prevent the development of full thickness defects and the onset of osteoarthritis.